Neurological diseases are a significant and increasing burden on our society. These include multiple sclerosis (MS), autism, Alzheimer's disease, mild traumatic brain injury etc. Many are associated with age. These diseases have a high societal impact in terms of cost to patients and the health system. Damaged mitochondria and oxidative metabolism are often implicated. There are few methods available to study mitochondrial function in living brain. Since mouse is the main preclinical model, and oxidative metabolism is high in gray matter (GM), we will develop methods specifically targeted to the difficult task of studying oxidative metabolism in vivo in mouse cortical gray matter. This project is to integrate, optimize and show proof of principle for a new multimodel MRI/near-infrared spectroscopy method for studying oxidative metabolism and mitochondrial function in gray matter of mouse models of neurological disease. Using a mouse model of multiple sclerosis for proof of principle, we will gain new knowledge of the relationships between mitochondrial damage, hypoxia, oxidative metabolism, and demyelination. In Aim 1, we will integrate and the MRI/NIRS system using geometries appropriate for mouse brain gray matter. Perfusion will be quantified using MRI; arterial oxygen saturation with a pulse oximeter; and microvascular oxygen saturation, venous hemoglobin saturation and total hemoglobin from broadband NIRS (to calculate GM CMRO2) Hemoglobin saturation provides a hypoxia marker. We will introduce cytochrome oxidase Cua redox data collection to assess mitochondrial redox, model light penetration in the mouse head to optimize for gray matter, integrate the data collection to one portable software package and determine reproducibility in a cohort of mice. In Aim 2, as proof of principle, we will study the cuprizone mouse model of MS. The model is demyelinating, has damaged mitochondria and hypoxia has been suggested to occur. Current treatments in MS focus on inflammation and demyelination but axonal loss and atrophy still occur. There may be a defect in mitochondrial function. We will show how CMRO2, perfusion, hypoxia and mitochondrial redox status are related to demyelination and symptoms. We will develop an MRI/NIRS system for assessing oxidative metabolism in gray matter of mouse models of neurological disease opening up new avenues of research to study the interplay between mitochondrial damage, oxidative metabolism, perfusion and hypoxia. We will show proof of principle by obtaining new and novel data showing how oxidative metabolism relates to demyelination in a mouse model of MS.